Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation
Gi/o protein-coupled receptors (Gi/o-GPCRs) limit pancreatic islet insulin secretion by decreasing {beta}-cell Ca2+ entry, which is essential for maintenance of glucose homeostasis. However, the Gi/o-GPCR signaling mechanism that mediates inhibition of human islet hormone secretion has not been identified. Here we demonstrate that Gi/o-GPCRs cause hyperpolarization of the {beta}-cell membrane potential through activation of Na+/K+ ATPases (NKAs) in mouse and human islets. Stimulation of Gi/o-coupled somatostatin or 2-adrenergic receptors induced oscillations in {beta}-cell NKA activity, which resulted in islet Ca2+ fluctuations. Selective induction of {beta}-cell Gi/o signaling with a chemogenetic Gi/o-GPCR also activated NKAs and initiated islet Ca2+ oscillations, suggesting that {beta}-cell Gi/o-GPCRs tune pulsatile insulin secretion. Furthermore, intra-islet paracrine activation of {beta}-cell Gi/o-GPCR signaling and NKAs by {delta}-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. Gi/o-GPCR-mediated oscillations in {beta}-cell membrane potential and Ca2+ were dependent on NKA phosphorylation by Src tyrosine kinases; an effect that was mimicked by stimulating islet insulin receptor tyrosine kinases. Whereas {beta}-cell NKA function was completely inhibited by cAMP-dependent PKA activation. Taken together, these data reveal that NKA-mediated hyperpolarization of {beta}-cell membrane potential serves as the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.